Parkinson's disease (PD) is an insidious disease that affects the quality of life of over one and a half million people in the United States alone. In the past several decades, it has become accepted that PD occurs as a result of degeneration in dopaminergic cells in the substantia nigra pars compacta. Animal models have shown that this degeneration causes a cascade of changes in the functioning of inhibitory and excitatory neurotransmitters within the basal ganglia. However, three major shortcomings in our current understanding of PD still remain. First, there remains limited knowledge of how PD affects the functioning of specific nuclei of the basal ganglia in humans and how this relates to motor deficits that are impaired in PD. Second, although degeneration in the substantia nigra can be used to confirm PD at autopsy, there is limited knowledge in living humans linking structural degeneration in the substantia nigra with neuronal activation in the basal ganglia and cortex. Third, there is limited knowledge of how the basal ganglia and cortex are impaired in PD prior to patients taking dopaminergic medication (de novo PD). Over the past few years, our laboratory has developed new paradigms and methodology using functional magnetic resonance imaging (fMRI) to examine specific nuclei in the basal ganglia when healthy adults produce and select grip force output. The general view that has emerged is that posterior nuclei of the basal ganglia regulate basic parameters of continuous grip force output, whereas anterior nuclei of the basal ganglia regulate the internal selection of grip force amplitude. As such, the central hypothesis of this application is that due to degeneration in the substantia nigra, PD patients lose the ability to activate the anterior and posterior basal ganglia and cortex appropriately for different motor tasks. In order to test this hypothesis, we will study de novo patients with PD and healthy control subjects in two specific aims using both fMRI and diffusion tensor imaging (DTI). Aims 1a and 2a will use fMRI to study the functional abnormalities of the basal ganglia-thalamo-cortical loop during grip force tasks in de novo PD and control subjects. Aims 1b and 2b will combine DTI and fMRI in de novo PD to examine the relation between structural degeneration (DTI) in the substantia nigra and neuronal activation (fMRI) in the basal ganglia and cortex when PD patients perform different grip force tasks. The results of the proposed studies will provide the first evidence in humans linking task-specific motor deficits in PD with structural degeneration in the substantia nigra and neuronal activation in the basal ganglia and cortex. PUBLIC HEALTH RELEVANCE: Parkinson's disease affects over one and a half million people in the US alone, and patients with Parkinson's disease have significant problems controlling movement. These problems are thought to be related to structural degeneration in a region of the brain called the substantia nigra, which in turn is part of a brain region known to be important for movement control called the basal ganglia. This will be the first study in humans to determine how specific motor tasks alter the link between structural degeneration in the substantia nigra and neuronal activation in specific nuclei of the basal ganglia. The study will use functional and high-resolution structural brain imaging to examine the basal ganglia and other brain regions in patients with Parkinson's disease as they perform different motor tasks and compare them to people without the disease. Since very little is known regarding the brain function of Parkinson's disease prior to taking medication, we will perform our studies before patients begin a drug treatment program for the disease.